CCL21 expression in β-cells induces antigen-expressing stromal cell networks in the pancreas and prevents autoimmune diabetes in mice

Freddy E. Gonzalez Badillo, Flavia Zisi Tegou, Maria M. Abreu, Riccardo Masina, Divya Sha, Mejdi Najjar, Shane H. Wright, Allison L. Bayer, Éva Korpos, Alberto Pugliese, R. Damaris Molano, Alice A. Tomei

Research output: Contribution to journalArticle

Abstract

Tumors induce tolerance toward their antigens by producing the chemokine CCL21, leading to the formation of tertiary lymphoid organs (TLOs). Ins2-CCL21 transgenic, nonobese diabetic (NOD) mice express CCL21 in pancreatic β-cells and do not develop autoimmune diabetes. We investigated by which mechanisms CCL21 expression prevented diabetes. Ins2-CCL21 mice develop TLOs by 4 weeks of age, consisting of naive CD4+ T cells compartmentalized within networks of CD45- gp38+CD31- fibroblastic reticular cell (FRC)-like cells. Importantly, 12-week-old Ins2-CCL21 TLOs contained FRC-like cells with higher contractility, regulatory, and anti-inflammatory properties and enhanced expression of β-cell autoantigens compared with nontransgenic NOD TLOs found in inflamed islets. Consistently, transgenic mice harbored fewer autoreactive T cells and a higher proportion of regulatory T cells in the islets. Using adoptive transfer and islet transplantation models, we demonstrate that TLO formation in Ins2-CCL21 transgenic islets is critical for the regulation of autoimmunity, and although the effect is systemic, the induction is mediated locally likely by lymphocyte trafficking through TLOs. Overall, our findings suggest that CCL21 promotes TLOs that differ from inflammatory TLOs found in type 1 diabetic islets in that they resemble lymph nodes, contain FRC-like cells expressing β-cell autoantigens, and are able to induce systemic and antigen-specific tolerance leading to diabetes prevention.

Original languageEnglish (US)
Pages (from-to)1990-2003
Number of pages14
JournalDiabetes
Volume68
Issue number10
DOIs
StatePublished - Oct 1 2019

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Gonzalez Badillo, F. E., Tegou, F. Z., Abreu, M. M., Masina, R., Sha, D., Najjar, M., Wright, S. H., Bayer, A. L., Korpos, É., Pugliese, A., Molano, R. D., & Tomei, A. A. (2019). CCL21 expression in β-cells induces antigen-expressing stromal cell networks in the pancreas and prevents autoimmune diabetes in mice. Diabetes, 68(10), 1990-2003. https://doi.org/10.2337/db19-0239